Therapeutic agents can be administered to mammals using a variety of techniques. The bioavailability of a therapeutic agent and its effectiveness are often a result of the method used to administer the agent. The most popular method of administering therapeutic agents is orally. Oral administration is popular because it is non-invasive and the therapeutic agent is often readily absorbed into the bloodstream of the recipient. Furthermore, the ease of administration results in enhanced patient compliance. However, despite the many advantages of oral administration, therapeutic agents containing proteins and peptides often cannot be given orally. This is primarily due to proteolytic enzymes present in the gastrointestinal tract which can easily degrade the proteins or peptides, resulting in poor bioavailability of the therapeutic agent. As a result, many therapeutic agents which contain proteins and peptides are delivered parenterally.
Parenteral administration bypasses the gastrointestinal tract and delivers the peptides or proteins directly into the bloodstream and the surrounding tissues of the recipient. This method of administration, however, has several disadvantages. For example, when peptides and proteins are delivered parenterally, they may exhibit an extremely short biological half life. As a result, repeated injections of the necessary peptide or protein are usually required. Furthermore, because parenteral administration is often an invasive therapy, poor patient compliance often occurs. Thus, many patients do not receive an adequate dose of the required therapeutic agent.
An alternative method to parenteral administration of a therapeutic agent is mucosal, especially intranasal administration. The mucosa, such as the nasal membrane, offers more absorption potential than any other noninvasive routes for peptides and proteins. For example, the nasal cavity offers both pharmacokinetic and pharmaceutical advantages. In addition, intranasal administration bypasses the metabolic administration pathways of the gastrointestinal tract and liver and thereby prevents degradation of the peptide or protein within the gastrointestinal tract. Furthermore, the nasal mucosa contains a large surface area and relatively low enzymatic degradation resulting in the rapid absorption of the peptide or protein. Because intranasal administration is both convenient and noninvasive, high patient compliance occurs.
Although there are numerous advantages to intranasal administration relative to parenteral and oral administration, several factors limit the exploitation of the nasal route for systemic absorption of peptides and proteins. For example, because the surface mucus coat in the nose is rapidly cleared, the time period available for therapeutic agent absorption is relatively short. Furthermore, high molecular weight peptides and proteins are not easily absorbed through the nasal membrane due to the lack of permeability. As a result, peptides and proteins are often administered with permeation enhancement compounds to increase bioavailability of the therapeutic agents. These enhancers often result in adverse side effects to the mucus membrane and may disrupt nasal functions. In addition, adverse pathological conditions may affect the nasal functions significantly and disrupt the ability to administer therapeutic agents intranasally. Furthermore, the presence of proteolytic enzymes in the nasal cavity may cause degradation of polypeptides intranasally administered.
Despite these disadvantages, scientists have attempted to improve the absorption of compounds in the nasal cavity using a variety of techniques including: (1) adding bioadhesive polymers to intranasal formulations to increase the residence time of the formulation in the nasal cavity; (2) adding nontoxic enhancers to intranasal formulations to improve the permeability of the nasal cavity; and (3) using enzyme inhibitors to prevent the degradation of the peptides by various proteolytic enzymes in the nasal cavity.
One therapeutic agent which has been extensively studied for its ability to be administered intranasally is insulin. Insulin is the primary therapeutic agent used for the treatment of diabetes mellitus and in particular, type I diabetes. Currently, diabetes in mammals is often treated with daily parenteral injections of insulin. However, due to the local discomfort and the disruption in lifestyle resulting from daily hypodermic injections of insulin, many patients with diabetes refuse to accept the insulin therapy entirely. As a result, numerous investigators have attempted to find an effective method of administering insulin intranasally.
In 1932, Collins et al. studied the absorption of insulin through nasal mucous-membranes in diabetic patients. Collins et al. (1932) Proc. Soc. Exp. Biol. Med., 29:756. In their study, insulin solutions containing saponin were sprayed by an atomizer or applied directly to the membranes of a diabetic patient using a small cotton pledget. Although a reduction in blood glucose levels following the intranasal administration of insulin to the diabetic patients was similar to the blood glucose levels found following a subcutaneous administration of insulin, the treatment produced mild congestion in the nasal mucosa and some symptoms of rhinitis.
In 1981, Hirai et al. compared glucose levels in rats following intranasal administration of insulin versus oral and intravenous administration of insulin. Hirai et al. (1981) Int. J. Pharm., 9:173. Hirai et al. found that plasma glucose levels in rats intravenously administered insulin decreased significantly, while plasma glucose levels following oral administration only slightly decreased. To achieve normoglycemia, a larger dose of insulin was required when it was administered intranasally compared to the dose required for intravenous administration. Specifically, a 10-fold increase in concentration of insulin was required for the intranasal administration of insulin to reduce plasma glucose levels in the rats to levels similar to the levels found following a parenteral administration of insulin.
To further enhance the nasal absorption of insulin, previous studies have examined adding surfactants to insulin. For example, the intranasal administration of insulin containing the surf actant sodium glycocholate decreased blood glucose levels; however, the dose of insulin needed to achieve normoglycemia was approximately 3 to 4 times that of intravenous administration of insulin. Yokosuka et al. (1977) J. Jpn. Diabet. Soc., 20:146.
The prior art discloses various methods for incorporating an additive or other active ingredient into a substrate, such as a polymer. One such method of incorporating (infusing) an additive into a polymeric material is described in U.S. Pat. No. 4,820,752 (Berens et al.) which employs a supercritical fluid, i.e., a gas at atmospheric pressure and temperature that becomes a liquid at below or equal to the critical temperature of the fluid. In U.S. Pat. No. 4,598,006 Sand employed this general method to impregnate a polymer with a fragrance, a pest control agent or scopolamine, all of which are of relatively low molecular weight. This method has not been employed incorporating a protein or a peptide in a polymer and administering such a protein or a peptide to a mammal through mucosa.
It has been surprisingly discovered in accordance with the present invention that peptides and proteins can be successfully infused into a matrix material and subsequently administered intranasally to treat various diseases in mammals without the addition of permeation enhancement compounds. The present invention alleviates many of the problems associated with the current methods of administering therapeutic agents intranasally to mammals by providing a pharmaceutical composition comprising a microparticle 10 to 250 .mu.m in diameter containing a therapeutic agent and a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition containing a microparticle which is produced by infusing a therapeutic agent, such as a peptide or protein, into a matrix material. The present invention further alleviates many of the problems encountered with intranasal liquid and spray preparations, such as chemical and microbiological instability during storage.